tbuckley/cabot-search huggingface dataset:
Can Apple and Google continue as health app gatekeepers as well as distributors and developers?
Authors: Olamide Sadare, Tom Melvin, Hugh Harvey, Erik Vollebregt, Stephen Gilbert
Journal: npj Digital Medicine (2023)

Mobile apps are the primary means by which consumers access digital health and wellness software, with delivery dominated by the 'Apple App Store' and the 'Google Play Store'. Through these virtual storefronts Apple and Google act as the distributor (and sometimes, importer) of many thousands of health and wellness apps into the EU, some of which have a medical purpose. As a result of changes to EU law which came into effect in May 2021, they must now ensure that apps are compliant with medical devices regulation and to inform authorities of serious incidents arising from their use. The extent to which these new rules are being complied with in practice is uneven, and in some areas unclear. In light of EU legislation related to competition, which came into effect in November 2022, it is also unclear how conflicts of interest can be managed between Apple and Google's roles as gateway duopoly importers and distributors whilst also developers of their own competitive health products. Finally, with the proposed European health data space regulation, wellness apps will be voluntarily registered and labelled in a fashion more like medical devices than consumer software. We explore the implications of these new regulations and propose future models that could resolve the apparent conflicts. All stakeholders would benefit from improved app store models to sustainably evolve safer, better, and fairer provision of digital health applications in the EU. As EU legislation comes into force it could serve as a template for other regions globally.
Understanding the increased susceptibility to asthma development in preterm infants
Authors: Jeremy Anderson, Lien Anh Ha Do, Danielle Wurzel, Paul V. Licciardi
Journal: Allergy (2023)

Preterm birth is associated with aberrant pulmonary development and increased susceptibility to a range of chronic lung diseases. Even in healthy preterms, the prevalence of physician-diagnosed asthma is far higher than in infants born at term. While physiological, environmental, and genetic factors have been studied extensively, few studies have investigated the immunological factors underpinning this increased susceptibility. Lower rates of atopy and allergic sensitization in preterm compared to term infants suggests non-allergic mechanisms may be driving asthma development in preterms. Preterm infants are more likely to develop severe RSV and HRV disease and have altered microbiomes compared to term infants. Therefore, investigating the differences in immunological interactions (e.g., response to viral infections, microbiome) between children born preterm and term will aid in understanding the immunological basis for their increased susceptibility to asthma development. This is critical to inform the development of interventions to reduce the burden of asthma in this highly vulnerable demographic.
CRISPR‐Cas13d effectively targets SARS‐CoV‐2 variants, including Delta and Omicron, and inhibits viral infection
Authors: Zongzhi Liu, Xiang Gao, Chuanwen Kan, Lingyu Li, Yuan Zhang, Yibo Gao, Shengyuan Zhang, Liangji Zhou, Hui Zhao, Mingkun Li, Zheng Zhang, Yingli Sun
Journal: MedComm (2023)

The recent pandemic of variants of concern (VOC) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the need for innovative anti-SARS-CoV-2 approaches in addition to vaccines and antiviral therapeutics. Here, we demonstrate that a CRISPR-Cas13-based strategy against SARS-CoV-2 can effectively degrade viral RNA. First, we conducted a cytological infection experiment, screened CRISPR-associated RNAs (crRNAs) targeting conserved regions of viruses, and used an in vitro system to validate functional crRNAs. Reprogrammed Cas13d effectors targeting NSP13, NSP14, and nucleocapsid transcripts achieved >99% silencing efficiency in human cells which are infected with coronavirus 2, including the emerging variants in the last 2 years, B.1, B.1.1.7 (Alpha), D614G B.1.351 (Beta), and B.1.617 (Delta). Furthermore, we conducted bioinformatics data analysis. We collected the sequence information of COVID-19 and its variants from China, and phylogenetic analysis revealed that these crRNA oligos could target almost 100% of the SARS-CoV family, including the emerging new variant, Omicron. The reprogrammed Cas13d exhibited high specificity, efficiency, and rapid deployment properties; therefore, it is promising for antiviral drug development. This system could possibly be used to protect against unexpected SARS-CoV-2 variants carrying multiple mutations.
Brexit adds further complexity to the health and care staffing crisis
Authors: Martha McCarey
Journal: BMJ (2023)

Brexit adds further complexity to the health and care staffing crisis Martha McCarey Brexit and health researcherHealth systems in the UK have a long standing dependency on international staff, and over the decades this has tended to intensify at times of shortage.Today is no exception, but this period of shortfall coincides with departure from the European Union (EU)-causing rapid, and at times, concerning changes in patterns of recruitment.
Th17.1 cell driven sarcoidosis-like inflammation after anti-BCMA CAR T cells in multiple myeloma
Authors: Alexander M. Leipold, Rudolf A. Werner, Johannes Düll, Pius Jung, Mara John, Emilia Stanojkovska, Xiang Zhou, Hannah Hornburger, Anna Ruckdeschel, Oliver Dietrich, Fabian Imdahl, Tobias Krammer, Stefan Knop, Andreas Rosenwald, Andreas Buck, Leif Erik Sander, Hermann Einsele, K. Martin Kortüm, Antoine-Emmanuel Saliba, Leo Rasche
Journal: Leukemia (2023)

Pseudo-progression and flare-up phenomena constitute a novel diagnostic challenge in the follow-up of patients treated with immune-oncology drugs. We present a case study on pulmonary flare-up after Idecabtagen Vicleucel (Ide-cel), a BCMA targeting CAR T-cell therapy, and used single-cell RNA-seq (scRNA-seq) to identify a Th17.1 driven autoimmune mechanism as the biological underpinning of this phenomenon. By integrating datasets of various lung pathological conditions, we revealed transcriptomic similarities between post CAR T pulmonary lesions and sarcoidosis. Furthermore, we explored a noninvasive PET based diagnostic approach and showed that tracers binding to CXCR4 complement FDG PET imaging in this setting, allowing discrimination between immune-mediated changes and true relapse after CAR T-cell treatment. In conclusion, our study highlights a Th17.1 driven autoimmune phenomenon after CAR T, which may be misinterpreted as disease relapse, and that imaging with multiple PET tracers and scRNA-seq could help in this diagnostic dilemma.
CAR T cells: engineered immune cells to treat brain cancers and beyond
Authors: Zoufang Huang, Saikat Dewanjee, Pratik Chakraborty, Niraj Kumar Jha, Abhijit Dey, Moumita Gangopadhyay, Xuan-Yu Chen, Jian Wang, Saurabh Kumar Jha
Journal: Molecular Cancer (2023)

Abstract Malignant brain tumors rank among the most challenging type of malignancies to manage. The current treatment protocol commonly entails surgery followed by radiotherapy and/or chemotherapy, however, the median patient survival rate is poor. Recent developments in immunotherapy for a variety of tumor types spark optimism that immunological strategies may help patients with brain cancer. Chimeric antigen receptor (CAR) T cells exploit the tumor-targeting specificity of antibodies or receptor ligands to direct the cytolytic capacity of T cells. Several molecules have been discovered as potential targets for immunotherapy-based targeting, including but not limited to EGFRvIII, IL13Rα2, and HER2. The outstanding clinical responses to CAR T cell-based treatments in patients with hematological malignancies have generated interest in using this approach to treat solid tumors. Research results to date support the astounding clinical response rates of CD19-targeted CAR T cells, early clinical experiences in brain tumors demonstrating safety and evidence for disease-modifying activity, and the promise for further advances to ultimately assist patients clinically. However, several variable factors seem to slow down the progress rate regarding treating brain cancers utilizing CAR T cells. The current study offers a thorough analysis of CAR T cells’ promise in treating brain cancer, including design and delivery considerations, current strides in clinical and preclinical research, issues encountered, and potential solutions.
KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition
Authors: Liberalis Debraj Boila, Subhadeep Ghosh, Subham K. Bandyopadhyay, Liqing Jin, Alex Murison, Andy G. X. Zeng, Wasim Shaikh, Satyaki Bhowmik, Siva Sai Naga Anurag Muddineni, Mayukh Biswas, Sayantani Sinha, Shankha Subhra Chatterjee, Nathan Mbong, Olga I. Gan, Anwesha Bose, Sayan Chakraborty, Andrea Arruda, James A. Kennedy, Amanda Mitchell, Eric R. Lechman, Debasis Banerjee, Michael Milyavsky, Mark D. Minden, John E. Dick, Amitava Sengupta
Journal: Leukemia (2023)
MRI-visible mesoporous polydopamine nanoparticles with enhanced antioxidant capacity for osteoarthritis therapy
Authors: Sitong Liu, Chen Zhang, Yuanyuan Zhou, Fang Zhang, Xiaohui Duan, Yang Liu, Xibang Zhao, Jie Liu, Xintao Shuai, Jiali Wang, Zhong Cao
Journal: Biomaterials (2023)
Next-generation antigen-presenting cell immune therapeutics for gliomas
Authors: Catalina Lee-Chang, Maciej S. Lesniak
Journal: Journal of Clinical Investigation (2023)

Antigen presentation machinery and professional antigen-presenting cells (APCs) are fundamental for an efficacious immune response against cancers, especially in the context of T cell-centric immunotherapy. Dendritic cells (DCs), the gold standard APCs, play a crucial role in initiating and maintaining a productive antigen-specific adaptive immunity. In recent decades, ex vivo-differentiated DCs from circulating CD14+ monocytes have become the reference for APC-based immunotherapy. DCs loaded with tumor-associated antigens, synthetic peptides, or RNA activate T cells with antitumor properties. This strategy has paved the way for the development of alternative antigen-presenting vaccination strategies, such as monocytes, B cells, and artificial APCs, that have shown effective therapeutic outcomes in preclinical cancer models. The search for alternative APC platforms was initiated by the overall limited clinical impact of DC vaccines, especially in indications such as gliomas, a primary brain tumor known for resistance to any immune intervention. In this Review, we navigate the APC immune therapeutics' past, present, and future in the context of primary brain tumors.
Targeting FAPα-expressing hepatic stellate cells overcomes resistance to antiangiogenics in colorectal cancer liver metastasis models
Authors: Ming Qi, Shuran Fan, Maohua Huang, Jinghua Pan, Yong Li, Qun Miao, Wenyu Lyu, Xiaobo Li, Lijuan Deng, Shenghui Qiu, Tongzheng Liu, Weiqing Deng, Xiaodong Chu, Chang Jiang, Wenzhuo He, Liangping Xia, Yunlong Yang, Jian Hong, Qi Qi, Wenqian Yin, Xiangning Liu, Changzheng Shi, Minfeng Chen, Wencai Ye, Dongmei Zhang
Journal: Journal of Clinical Investigation (2023)
Resource: A Cellular Developmental Taxonomy of the Bone Marrow Mesenchymal Stem Cell Population in Mice
Authors: Paola Pisterzi, Lanpeng Chen, Claire van Dijk, Michiel J. W. Wevers, Eric J. M. Bindels, Marc H. G. P. Raaijmakers
Journal: HemaSphere (2023)

Mesenchymal stem cells (MSCs) play pivotal roles in tissue (re)generation. In the murine bone marrow, they are thought to reside within the Sca-1 + CD51 + bone marrow stromal cell population. Here, using scRNAseq, we aimed to delineate the cellularheterogeneity of this MSC-enriched population throughout development. At the fetal stage, the MSC population is relatively homogeneous with subsets predicted to contain stem/progenitor cells, based on transcriptional modeling and marker expression. These subsets decline in relative size throughout life, with postnatal emergence of specialized clusters, including hematopoietic stem/progenitor cell (HSPC) niches. In fetal development, these stromal HSPC niches are lacking, but subsets of endothelial cells express HSPC factors, suggesting that they may provide initial niches for emerging hematopoiesis. This cellular taxonomy of the MSC population upon development is anticipated to provide a resource aiding the prospective identification of cellular subsets and molecular mechanisms driving bone marrow (re)generation.
Hematopoietic Cell Autonomous Disruption of Hematopoiesis in a Germline Loss-of-function Mouse Model of RUNX1-FPD
Authors: Martijn P. T. Ernst, Eline Pronk, Claire van Dijk, Paulina M. H. van Strien, Tim V. D. van Tienhoven, Michiel J. W. Wevers, Mathijs A. Sanders, Eric M. J. Bindels, Nancy A. Speck, Marc H. G. P. Raaijmakers
Journal: HemaSphere (2023)

RUNX1 familial platelet disorder ( RUNX1 -FPD) is a hematopoietic disorder caused by germline loss-of-function mutations in the RUNX1 gene and characterized by thrombocytopathy, thrombocytopenia, and an increased risk of developing hematologic malignancies, mostly of myeloid origin. Disease pathophysiology has remained incompletely understood, in part because of a shortage of in vivo models recapitulating the germline RUNX1 loss of function found in humans, precluding the study of potential contributions of non-hematopoietic cells to disease pathogenesis. Here, we studied mice harboring a germline hypomorphic mutation of one Runx1 allele with a loss-of-function mutation in the other Runx1 allele ( Runx1 L148A/− mice), which display many hematologic characteristics found in human RUNX1 -FPD patients. Runx1 L148A/− mice displayed robust and pronounced thrombocytopenia and myeloid-biased hematopoiesis, associated with an HSC intrinsic reconstitution defect in lymphopoiesis and expansion of myeloid progenitor cell pools. We demonstrate that specific deletion of Runx1 from bone marrow stromal cells in Prrx1-cre ; Runx1 fl/fl mice did not recapitulate these abnormalities, indicating that the hematopoietic abnormalities are intrinsic to the hematopoietic lineage, and arguing against a driving role of the bone marrow microenvironment. In conclusion, we report a RUNX1 -FPD mouse model faithfully recapitulating key characteristics of human disease. Findings do not support a driving role of ancillary, non-hematopoietic cells in the disruption of hematopoiesis under homeostatic conditions.
Impact of ferric carboxymaltose for iron deficiency at discharge after heart failure hospitalization: a European multinational economic evaluation
Authors: Phil McEwan, Cale Harrison, Rhona Binnie, Ruth D. Lewis, Alain Cohen‐Solal, Lars H. Lund, Marcus Ohlsson, Stephan von Haehling, Josep Comin‐Colet, Domingo A. Pascual‐Figal, Sandra Wächter, Fabio Dorigotti, Antonio Ramirez de Arellano, Piotr Ponikowski, Ewa A. Jankowska
Journal: European Journal of Heart Failure (2023)

Iron deficiency (ID) is comorbid in up to 50% patients with heart failure (HF) and exacerbates disease burden. Ferric carboxymaltose (FCM) reduced HF hospitalizations and improved quality of life when used to treat ID at discharge in patients hospitalized for acute HF with left ventricular ejection fraction <50% in the AFFIRM-AHF trial. We quantified the effect of FCM on burden of disease and the wider pharmacoeconomic implications in France, Germany, Poland, Spain and Sweden.The per country eligible population was calculated, aligning with the 2021 European Society of Cardiology (ESC) HF guidelines and the AFFIRM-AHF trial. Changes in burden of disease with FCM versus standard of care (SoC) were represented by disability-adjusted life years (DALYs), hospitalization episodes and bed days, using AFFIRM-AHF data. A Markov model was adapted to each country to estimate cost-effectiveness and combined with epidemiology data to calculate the impact on healthcare budgets. Between 335 (Sweden) and 13 237 (Germany) DALYs were predicted to be avoided with FCM use annually. Fewer hospitalizations and shorter lengths of stay associated with FCM compared to SoC were projected to result in substantial annual savings in bed days, from 5215 in Sweden to 205 630 in Germany. In all countries, FCM was predicted to be dominant (cost saving with gains in quality-adjusted life years), resulting in net savings to healthcare budgets within 1 year.This comprehensive evaluation of FCM therapy highlights the potential benefits that could be realized through implementation of the ESC HF guideline recommendations regarding ID treatment.
YAP1 and WWTR1 expression inversely correlates with neuroendocrine markers in Merkel cell carcinoma
Authors: Thomas C. Frost, Ashley K. Gartin, Mofei Liu, Jingwei Cheng, Harita Dharaneeswaran, Derin B. Keskin, Catherine J. Wu, Anita Giobbie-Hurder, Manisha Thakuria, James A. DeCaprio
Journal: Journal of Clinical Investigation (2023)

BackgroundMerkel cell carcinoma (MCC) is an aggressive neuroendocrine (NE) skin cancer caused by severe UV-induced mutations or expression of Merkel cell polyomavirus (MCPyV) large and small T antigens (LT and ST). Despite deep genetic differences between MCPyV-positive and -negative subtypes, current clinical diagnostic markers are indistinguishable, and the expression profile of MCC tumors is, to our knowledge, unexplored.MethodsHere, we leveraged bulk and single-cell RNA-Seq of patient-derived tumor biopsies and cell lines to explore the underlying transcriptional environment of MCC.ResultsStrikingly, MCC samples could be separated into transcriptional subtypes that were independent of MCPyV status. Instead, we observed an inverse correlation between a NE gene signature and the Hippo pathway transcription factors Yes1-associated transcriptional regulator (YAP1) and WW domain-containing transcriptional regulator 1 (WWTR1). This inverse correlation was broadly present at the transcript and protein levels in the tumor biopsies as well as in established and patient-derived cell lines. Mechanistically, expression of YAP1 or WWTR1 in a MCPyV-positive MCC cell line induced cell-cycle arrest at least in part through TEA domain-dependent (TEAD-dependent) transcriptional repression of MCPyV LT.ConclusionThese findings identify what we believe to be a previously unrecognized heterogeneity in NE gene expression within MCC and support a model of YAP1/WWTR1 silencing as essential for the development of MCPyV-positive MCC.FundingUS Public Health Service grants R35CA232128, P01CA203655, and P30CA06516.
Response to “Comment on ‘Maternal Exposure to Per- and Polyfluoroalkyl Substances (PFAS) and Male Reproductive Function in Young Adulthood: Combined Exposure to Seven PFAS’”
Authors: Katia Keglberg Hærvig, Kajsa Ugelvig Petersen, Karin Sørig Hougaard, Christian Lindh, Cecilia Høst Ramlau-Hansen, Gunnar Toft, Aleksander Giwercman, Birgit Bjerre Høyer, Esben Meulengracht Flachs, Jens Peter Bonde, Sandra Søgaard Tøttenborg
Journal: Environmental Health Perspectives (2023)
Assessment of the Role of Artificial Intelligence in the Association Between Time of Day and Colonoscopy Quality
Authors: Zihua Lu, Lihui Zhang, Liwen Yao, Dexin Gong, Lianlian Wu, Meiqing Xia, Jun Zhang, Wei Zhou, Xu Huang, Chunping He, Huiling Wu, Chenxia Zhang, Xun Li, Honggang Yu
Journal: JAMA Network Open (2023)

Importance Time of day was associated with a decline in adenoma detection during colonoscopy. Artificial intelligence (AI) systems are effective in improving the adenoma detection rate (ADR), but the performance of AI during different times of the day remains unknown. Objective To validate whether the assistance of an AI system could overcome the time-related decline in ADR during colonoscopy. Design, Setting, and Participants This cohort study is a secondary analysis of 2 prospective randomized controlled trials (RCT) from Renmin Hospital of Wuhan University. Consecutive patients undergoing colonoscopy were randomly assigned to either the AI-assisted group or unassisted group from June 18, 2019, to September 6, 2019, and July 1, 2020, to October 15, 2020. The ADR of early and late colonoscopy sessions per half day were compared before and after the intervention of the AI system. Data were analyzed from March to June 2022. Exposure Conventional colonoscopy or AI-assisted colonoscopy. Main Outcomes and Measures Adenoma detection rate. Results A total of 1780 patients (mean [SD] age, 48.61 [13.35] years, 837 [47.02%] women) were enrolled. A total of 1041 procedures (58.48%) were performed in early sessions, with 357 randomized into the unassisted group (34.29%) and 684 into the AI group (65.71%). A total of 739 procedures (41.52%) were performed in late sessions, with 263 randomized into the unassisted group (35.59%) and 476 into the AI group (64.41%). In the unassisted group, the ADR in early sessions was significantly higher compared with that of late sessions (13.73% vs 5.70%; P = .005; OR, 2.42; 95% CI, 1.31-4.47). After the intervention of the AI system, as expected, no statistically significant difference was found (22.95% vs 22.06%, P = .78; OR, 0.96; 95% CI; 0.71-1.29). Furthermore, the AI systems showed better assistance ability on ADR in late sessions compared with early sessions (odds ratio, 3.81; 95% CI, 2.10-6.91 vs 1.60; 95% CI, 1.10-2.34). Conclusions and Relevance In this cohort study, AI systems showed higher assistance ability in late sessions per half day, which suggests the potential to maintain high quality and homogeneity of colonoscopies and further improve endoscopist performance in large screening programs and centers with high workloads.
ENPP1 Immunobiology as a Therapeutic Target
Authors: Borja Ruiz-Fernández de Córdoba, Rafael Martínez-Monge, Fernando Lecanda
Journal: Clinical Cancer Research (2023)

ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase) participates in the hydrolysis of different purine nucleotides in an array of physiologic processes. However, ENPP1 is frequently overexpressed in local relapses and tumor metastases, which are associated with poor prognosis and survival in a range of solid tumors. ENPP1 promotes an immunosuppressive tumor microenvironment (TME) by tilting the balance of ATP/adenosine (Ado) in conjunction with other components (CD38, CD39/ENTPD1, and CD73/NT5E). Moreover, ENPP1 intersects with the stimulator of interferon genes (STING), impairing its robust immune response through the hydrolysis of the effector 2´,3´-cyclic GMP-AMP. Thus, ENPP1 blockade emerges as a unique target eliciting immune remodeling and leveraging the STING pathway. Several ENPP1 inhibitors have shown an immunostimulatory effect, and their combination with other therapeutic modalities, such as immune-checkpoint blockade, STING activation, DNA damage response (DDR) inhibitors, and radiotherapy (RT), represents a promising avenue to boost antitumor-immune responses and to improve current clinical outcomes in several tumors. This comprehensive review summarizes the current state of the art and opens new perspectives for novel treatment strategies.